The objective of the proposed research is to extend work previously done to develop and evaluate approaches for prolonging the duration of action of narcotic antagonists. Naltrexone and naloxone will serve as model antagonists to test the applicability of the proposed methods for prolonging drug release. The drug delivery systems to be developed for the narcotic antagonist can be described as follows: (1) pro-drugs of the antagonist which are covalently bonded at the 3-phenolic hydroxyl and the 6-keto positions thereby inhibiting phenolic conjugation and 6-keto reduction in vivo, (2) slightly soluble salts of these prodrugs incorporated in an oil suspension designed to yield steady state therapy, and (3) the antagonist incorporated in an oil-in-water-in-oil multiple emulsion system for intramuscular injection. Collectively, these approaches afford the opportunity to control drug release by such mechanisms as (1) controlling the rate of drug diffusion through the vehicle administered intramuscularly, (2) controlling the rate of drug partitioning in a similar vehicle, (3) controlling the rate of conversion of pro-drug to drug, (4) controlling the release of pro-drug into the body, and (5) by controlling the rate of dissolution of antagonist administered intramuscularly as an insoluble salt. Several of the methods outlined may be combined in order to achieve the optimum prolonged release profile for the antagonist. The prolonged action drug delivery systems which are developed will be submitted for evaluation of biological performance. The most promising of the systems will be submitted for complete pharmacokinetic analysis in animals. There will be developed a pharmacokinetic theory designed to predict the optimum pro-drug kinetics and to calculate the corresponding dosage regimen. BIBLIOGRAPHIC REFERENCES: Metabolic Reduction of Naltrexone II. In Vitro Studies Using Liver from Guinea Pig, Monkey and Rat, L. Malspeis, T.M. Ludden, M.S. Bathala, B.E. Morrison, D.R. Feller and R.H. Reuning, Res. Commun. Chem. Path. Pharmacol. 14, 393-406 (1976). Determination of Naloxone and Naltrexone as Perfluoroalkyl Ester Derivatives by Electron-Capture Gas-Liquid Chromatography, Richard A. Sams and Louis Malspeis, J. Chromatography 125, 409-420 (1976).